Medicament compositions based on tiotropium bromide and formoterol fumarate

ABSTRACT

The present invention relates to new medicament compositions based on anticholinergic compounds, which have a long-lasting effect, and beta-mimetics, which have a long-lasting effect, processes for their production and their use in the therapy of respiratory ailments.

RELATED APPLICATION

This application is a continuation of U.S. Ser. No. 09/568,880, filedMay 9,2000.

FIELD OF THE INVENTION

The present invention relates to new medicament compositions based onanticholinergic compounds, which have a long-lasting effect, andβ-mimetics, which have a long-lasting effect, processes for theirproduction and their use in the therapy of respiratory ailments such asasthma or chronic obstructive pulmonary disease (COPD).

BACKGROUND OF THE INVENTION

It is known from the prior art that β-mimetics and anticholinergics cansuccessfully be used as bronchospasmolytics for the treatment ofobstructive respiratory ailments, such as, e.g., asthma. Substances withβ-sympatho-mimetic effectiveness, such as, e.g., the active substanceformoterol, also known from the prior art, can, however, be associatedwith undesirable side-effects when administered to humans.

Generally, the central effects manifest as unease, excitation,sleeplessness, fear, shaking fingers, outbreaks of sweating andheadaches. Here, inhalative application does not exclude theseside-effects although they are generally less severe than with peroralor parenteral application.

The side-effects of the β-sympatho-mimetics used as asthma agents areprimarily associated with a more or less pronounced β1-stimulatingeffect on the heart. It generates tachycardia, palpitation, anginapectoris-like complaints and arrhythmia [P. T. Ammon (Ed.), MedicamentSide-effects and Interactions, Wissenschaftliche Verlagsgesellschaft,Stuttgart 1986, S. 584].

DESCRIPTION OF THE INVENTION

Surprisingly, it has now been found that the above-mentioned sidefectscan be substantially reduced by a combination of a β-sympatho-mimetic,which has a long-lasting effect, with an anticholinergic, which has along-lasting effect.

In addition, it was also very surprisingly discovered that thebronchospasmolytic effects of the anticholinergic, which has along-lasting effect, and the β-mimetic, which has a long-lasting effect,increase in a superadditive manner.

Hence with the combination of active ingredients according to theinvention, a substantial increase in effectiveness can be expected—incomparison to the individual substances and combinations known from theprior art—in the case of both COPD and asthma.

The following active ingredients can preferably be used as β-mimetics,which have a long-lasting effect, in the active ingredients combinationaccording to the invention: bambuterol, bitolterol, carbuterol,clenbuterol, fenoterol, formoterol, hexoprenalin, ibuterol, pirbuterol,procaterol, reproterol, salmeterol, sulfonterol, terbutalin,tolubuterol,4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]-amino}ethyl]-2(3H-benzothiazolone,1-(2-fluoro4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylamino)ethanolor1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol,optionally in the form of their racemates, their enantiomers, theirdiastereomers, and mixtures thereof, and optionally theirpharmacologically-compatible acid addition salts.

The following are preferably used as β-mimetics,.which have along-lasting effect, in the active ingredients combination according tothe invention: formoterol, salmeterol,4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone,1-(2-fluoro4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanolor1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,optionally in the form of their racemates, their enantiomers, theirdiastereomers and mixtures thereof, and optionally theirpharmacologically-compatible acid addition salts.

Especially preferably, the following are used as β-mimetics in themedicament compositions according to the invention: formoterol orsalmeterol, optionally in the form of their racemates, theirenantiomers, their diastereomers and mixtures thereof, and optionallytheir phaimacologically-compatible acid addition salts.

As stated above, the β-mimetics which have a long-lasting effect can beconverted and used in the form of their physiologically andpharmacologically-compatible salts. The following can be considered, byway of example, to represent the acid addition salts: hydrochloric acid,hydrobromic acid, sulphuric acid, phosphoric acid, methanosulphonicacid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acidor maleic acid. Furthermore, mixtures of the aforementioned acids can beused.

From the viewpoint of the superadditive bronchospasmolytic effect, thefumarate of formoterol (abbreviated to formoterol FU) is especiallypreferred as a β-mimetic which has a long-lasting effect. Here, theactive substance formoterol can be used as an enantiomer or diastereomermixture or in the form of the individual enantiomers/diastereomers. Withthe same preferred significance, according to the invention, salmeterolcan also be used as a β-mimetic which has a long-lasting effect,optionally in the form of its racemates, enantiomers, of which the (R)enantiomer is most especially preferred, and optionally itspharmacologically-acceptable addition salts.

As anticholinergics which have a long-lasting effect, basically thosewhich are already known from the prior art, such as glycopyrroniumbromide and esters of bi- and tricyclic amino alcohols, are suitable,such as are known from European disclosure document 0 418 716 andInternational Patent Application WO 92/16528, and to the full contentsof which reference is hereby made.

Within the framework of the invention, glycopyrroniumbromide canespecially be considered as an anticholinergic which has a long-lastingeffect, and compounds of formula (I)

can be considered as esters of bi- and tricyclic amino alcohols wherein

A denotes a group of general formula (II)

 in which

Q denotes one of the double-bonded groups —CH₂—CH₂—, —CH₂—CH₂—CH₂—,—CH═CH—, or

R denotes an optionally halogen- or hydroxy-substituted C₁-C₄ alkylgroup,

R′ denotes a C₁-C₄ alkyl group and R and R′ can also combine to form aC₄-C₆ alkylene group, and

an equivalent of an anion X is counters the positive charge of the Natom,

Z denotes one of the groups

 wherein

Y represents a single bond, an O or S atom or one of the groups —CH₂—,—CH₂—CH₂—, —CH═CH—, —OCH₂— or —SCH₂—;

R¹ denotes hydrogen, OH, C₁-C₄ alkoxy or C₁-C₄ alkyl, which canoptionally be substituted by hydroxy;

R² denotes a thienyl, phenyl, furyl, cyclopentyl or cyclohexyl group,wherein these groups can also be substituted by methyl, and thienyl andphenyl can also be substituted by fluorine or chlorine,

R³ denotes hydrogen or a thienyl or phenyl group, which can optionallybe substituted by halogen or C₁-C₄ alkyl,

optionally in the form of their racemates, their enantiomers, theirdiastereomers and mixtures thereof.

Within the framework of the invention, glycopyrroniumbromide canespecially preferably be considered as an anticholinergic which has along-lasting effect, and compounds of formula (I) can be considered asesters of bi- and tricyclic amino alcohols, wherein

A denotes a group of general formula (II)

 in which

Q denotes one of the double-bonded groups —CH═CH—, —CH₂—CH₂— or

R denotes a methyl, ethyl or propyl group, optionally substituted byfluorine or hydroxy,

R′ denotes methyl, ethyl or propyl, preferably methyl, and an equivalentof an anion X selected from the group comprising chloride, bromide andmethanesulphonate, preferably bromide, counters the positive charge ofthe N atom,

Z denotes one of the groups

 wherein

Y represents a single bond or an O atom;

R¹ denotes hydrogen, OH, methoxy, ethoxy, propoxy, methyl, ethyl,propyl, hydroxymethyl, hydroxyethyl, or hydroxypropyl;

R² denotes a thienyl, phenyl, or cyclohexyl group, wherein these groupscan also be substituted by methyl, and thienyl and phenyl can also besubstituted by fluorine or chlorine,

R³ denotes hydrogen, or a thienyl or phenyl group which can optionallybe substituted by fluorine, chlorine or methyl,

optionally in the form of their racemates, their enantiomers, theirdiastereomers and mixtures thereof.

According to the invention, medicament compositions in which compoundsof formula (I) are used as anticholinergics which have a long-lastingeffect are of special significance, wherein

A denotes a group of general formula (II)

 in which

Q denotes one of the double-bonded groups —CH═CH—, —CH₂—CH₂— or

R denotes methyl or ethyl;

R′ denotes methyl; and

an equivalent of the anion X= bromide is positioned opposite thepositive charge of the N atom,

Z denotes one of the groups

 wherein

Y denotes an O atom;

R¹ denotes hydrogen, OH or hydroxymethyl;

R² denotes a thienyl, phenyl or cyclohexyl group; and

R³ denotes hydrogen, thienyl or phenyl group,

optionally in the form of their racemates, their enantiomers, theirdiastereomers and mixtures thereof.

Of the compounds named above, within the framework of the presentinvention those of the 3-α position are especially preferred.

The described anticholinergic active substances can optionally be usedin the form of their pure enantiomers, mixtures thereof or theirracemates.

It is especially preferred that tiotropium salt, especially tiotropiumbromide[(1α,2β,4β,5α,7β)-7-[(hydroxy-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0^(2,4)]nonanebromide monohydrate (abbreviated to tiotropium BR)] is used as ananticholinergic.

As alkyl groups (even insofar as they are components of other groups),unless otherwise defined, branched and unbranched alkyl groups with 1 to4 carbon atoms are considered. By way of example, methyl, ethyl, propylor butyl are named. Insofar as not otherwise named, all of the possibleisomeric forms of the hereinbefore-named designations propyl and butylare included. For example, the designation propyl includes the twoisomeric groups n-propyl and isopropyl, the designation butyl, n-butyl,isobutyl, sec-butyl and tert-butyl. Optionally, common abbreviations areused to designate the hereinbefore-named alkyl groups, such as Me formethyl, Et for ethyl, etc.

As alkoxy groups (even insofar as they are components of other groups),unless otherwise defined, branched and unbranched alkyl groups, bridgedvia an oxygen atom and with 1 to 4 carbon atoms, are considered. Thefollowing are named by way of example: methoxy, ethoxy, propoxy(=propyloxy) or butoxy (=butyloxy). Here too, insofar as not otherwisenamed, all of the possible isomeric forms of the hereinbefore-nameddesignations propoxy and butoxy are included.

Branched and unbranched alkylene bridges with 4 to 6 carbon atoms areconsidered as alkylene groups. The following are named by way ofexample: butylene, pentylene, and hexylene. Insofar as not otherwisenamed, all of the possible isomeric forms of the hereinbefore-nameddesignations butylene, pentylene, hexylene are included. For example,the designation butylene includes the isomers n-butylene,1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene,1,2-dimethylethylene, etc.

Generally, fluorine, chlorine, bromine, or iodine are designated ashalogen.

Insofar as not otherwise mentioned, anion X is generally designated asfluorine, chlorine, bromine, iodine, methanesulphonate, fumarate, orcitrate.

The active substance compositions according to the invention arepreferably administered in the form of a dosing aerosol, however, anyother form or parenteral or oral application is possible. Here, theapplication of dosing aerosols embodies the preferred application form,especially in the therapy of obstructive lung diseases or for thetreatment of asthma.

Apart from applications in aerosols which operate via propellant gases,the active substance combinations according to the invention can also beadministered by means of so-called atonisers, via which solutions ofpharmacologically-active substances can be sprayed under high pressureso that a mist of inhalable particles results. The advantage of theseatomisers is that the use of propellant gases can be completelydispensed with.

The medicaments intended for inhalation are usually dissolved in anaqueous or ethanolic solution, wherein solvent mixtures of ethanol orwater are also suitable, depending on the solution characteristics ofthe active substances.

Such atomisers are described, for example, in PCT Patent Application No.WO91/14468 and International Patent Application PCT/EP96/04351,reference here being made to the contents thereof. With the atomisersdescribed here, which are also known under the designation Respimat®,defined volumes of solutions containing active substances are sprayed athigh pressure through small jets so that inhalable aerosols result witha preferred particle size of between 1 and 10, preferably between 2 and5 micrometres.

Amongst others, mixtures which, e.g., contain ethanol as a solvent aresuitable for use as solvents for medicament preparation.

Apart from water, other components of the solvent are optionally otherco-solvents and the medicament preparation can also contain flavoringsand other pharmacological adjuvants. Examples of co-solvents are thosewhich contain hydroxyl groups or other polar groups such asalcohols—especially isopropyl alcohol, glycols—especially propyleneglycol, polyethylene glycol, polypropylene glycol, glycol ether,glycerol, polyoxyethylene alcohols and esters of polyoxyethylene fattyacids. Co-solvents are suited to increasing the solubility of adjuvantsand, optionally, the active substance. Other pharmacological adjuvantscan be added, such as, e.g., preservatives, especially benzalkoniumchloride. The preferred quantity of preservatives, especiallybenzalkonium chloride, is between 8 and 12 mg/100 ml solution.

Complex formers can be added to the active substance combination toavoid spray anomalies. Suitable complex formers are those which arepharmacologically-acceptable, especially those which are alreadypermitted under drug licensing laws. EDTA, nitrilotriacetic acid, citricacid and ascorbic acid, and also their salts, are especially suitable.The disodium salt of ethylenediamtetraacetic acid is especiallysuitable.

The proportion of dissolved active substance composition in the finishedmedicament preparation is between 0.001 and 5%, preferably between 0.005and 3%, and especially 0.01 to 2%. The maximum concentration ofmedicament is dependent on solubility in solvent and the necessarydosage for attaining the desired therapeutic effect.

The following preparation forms are cited as a formulation example:

Component Parts Composition in mg/100 ml Tiotropium bromide 333.3 mgFormoterol fumarate 333.3 mg Benzalkonium chloride  10.0 mg EDTA  50.0mg HCl (1N) ad pH 3.4 Tiotropium bromide 333.3 mg Salmeterol xinafoate666.6 mg Benzalkonium chloride  10.0 mg EDTA  50.0 mg HCl (1N) ad pH 3.4

In addition, the active substance combinations can also be inhaled inthe form of a powder. The production of such administration forms isknown from the prior art. Apart from the active substance combination,corresponding to the present invention, they containpharmacologically-compatible carrier or adjuvant substances, such as,e.g., microcrystalline lactose. The dose provided for inhalation can,for example, be filled into capsules and has, e.g., the followingcomposition:

Component Parts Quantity Tiotropium bromide hydrate 6 μg Formoterolfumarate × 2 H₂O 6 μg Lactose monohydrate ad 25 mg

Results of the Experiment

Bronchospasmolytic and cardiovascular effect of tiotropium bromide,formoterol fumarate and combinations thereof after inhalativeapplication of an aqueous solution to narcotized dogs by means ofRespimat®.

Material and Methods

18 mongrel dogs with a body weight of 27 to 32 kg. Kept in individual orcommunal cages, pelleted standard food, last fed approximately 15 hoursbefore the start of the tests, drinking water freely available.

After pre-medication with 2 mg/kg morphine hydrochloride i.m., 30 mg/kgpentobarbital-sodium (Nembuta®) is slowly injected intravenously. Theanimals are relaxed with 1.0 mg/kg i.v. suxamethonium. After intubationvia a servo ventilator 900C (Siemens), the animals are ventilated withambient air and oxygen (4:1), frequency 15/min., breath volume 6-8l/min. For registration of the breathing mechanics, breath flow isdetermined by means of a pressurizing pipe (flesh no. 1), installeddirectly before the orotracheal tube, of a differential pressurerecorder and amplifier DCB-4C. A catheter is placed in the trachea and asecond (balloon) catheter is placed in the lung section of theesophagus. Both are connected with a differential pressure recorder andamplifier for determination of the transpulmonary pressure. A breathmechanics computer (IFD-Mühlheim) determines the pulmonary resistance(R) from the registered pressure values. From this, a computer programVAS-1 LA (IFD-Mühlheim) calculates:$\text{Pulmonary resistance} = \frac{\text{max. transpulmonary pressure}}{\text{breath flow}}$

Registration of heart frequency is via ECG (extremity derivative II) andcardiotachometer.

After an equilibration period of 30 minutes, short-term bronchospasmsare generated by i.v. injection of 10 μg/kg acetylcholine chloride—thisis repeated 2-3× within a 10-minute period. The test substancestiotropium bromide, formoterol fumarate and the combination of bothsubstances are administered as aqueous solutions with the BINEB atomizer(Respimat®). Application of the combinations takes place with theindividual combinations with an interval of approximately 1 minute. Withthe BINEB system, the triggering mechanism takes place at the end of theexpiration phase and the atomized solution is pressed into thetracheo-bronchial tree in the following inspiration phase of the breathpump.

Dosages Tiotropium bromide: 3 and 10 μg/15 μl Formoterol fumarate: 3 and10 μg/15 μl Tiotropium bromide + formoterol fumarate: 3 + 3 μg or 10 +10 μg/15 μl

Tables 1-6 show the starting values and the values after substancetreatment over time within 180 minutes. The percentile inhibitions ofthe pulmonary resistance increases, induced by ACh, over the time from180 minutes.

Results

The results are shown in the Tables and in the Diagrams. 3 and 10 μgtiotropium bromide, or formoterol firmarate, inhibit the bronchialresistance increased by intravenous hmjection of ACh, stepped withregard to dosage and clear. The maximum bronchospasmolytic effect offormoterol FU rapidly occurs with both dosages, that of tiotropium BRdelayed after approximately 60 minutes. The effective duration offormoterol FU is comparatively short, especially with the low dosages,but according to expectations those of the tiotropium BR were continuousuntil the end of the test (180 minutes).

With the combination of 3 μg tiotropium bromide+3 μg formoterol FU, avery rapidly-occurring bronchiospasmolysis of 90% was attained whichcontinued practically unchanged until the end of the test. Theprotective effect of the combination substantially exceeds that of theindividual components, but also the sum of the individual effects of 3μtiotropium bromide and 3 μg formoterol FU. It exceeds the effects of 10μg tiotropium bromide or 10 μg formoterol fumarate (cf. Diagram 2).

Tiotropium bromide on its own has no influence at all on the heartfrequency, either with 3 μg or 10 μg. On the other hand, formoterol FUincreases it in stages, dependent on dosage, and above all by a maximnumof over 90% with high dosage. Values of over 80% are still measuredafter the end of the test. The frequency effects are substantiallylessened with the combinations 3+3 μg, or also 10+10 μg tiotropiumbromide and formoterol fiumarate, and lie below 30%.

Evaluation

Entirely surprising results were found with the combination of theanticholinergic and the β-mimetic as opposed to the individualsubstances:

1. Rapid onset of effect

2. Long duration of effect

but primarily

3. The superadditive bronchospasmolytic effect, and

4. The substantially reduced frequency increase, especially with thehigh formnoterol dose.

A substantially-improved therapeutic effect can be expected with thecombination preparation for both COPD and asthma, associated with theadvantage of minimal cardial side-effects.

TABLE 1 Influence of 3 μg Tiotropium Bromide on the Heart Frequency ofNarcotized Dogs After Inhalative Application via Respimat ®, n = 6Minutes after application Control 1 5 10 20 30 60 120 180 Heartfrequency (beats/min.) 66.50 63.00 67.00 64.00 61.00 63.00 67.00 63.0066.00 87.50 87.00 84.00 82.00 87.00 81.00 89.00 87.00 87.00 86.50 84.0084.00 89.00 89.00 89.00 84.00 77.00 86.00 109.50 115.00 115.00 116.00120.00 121.00 104.00 105.00 105.00 110.50 119.00 119.00 118.00 110.00110.00 111.00 110.00 100.00 85.50 85.00 87.00 90.00 93.00 97.00 97.0092.00 96.00 Mean 91.00 92.17 92.67 93.17 93.33 93.50 92.00 89.00 90.00value sem 6.80 8.63 8.23 8.45 8.35 8.46 6.40 7.14 5.66 3 μg tiotropiumbromide, % alteration 66.50 −5.26 0.75 −3.76 −8.27 −5.26 0.75 −5.26−0.75 87.50 −0.57 −4.00 −6.29 −0.57 −7.43 1.71 −0.57 −0.57 86.50 −2.89−2.89 2.89 2.89 2.89 −2.89 −10.98 −0.58 109.50 5.02 5.02 5.94 9.59 10.50−5.02 −4.11 −4.11 110.50 7.69 7.69 6.79 −0.45 −0.45 0.45 −0.45 −9.5085.50 −0.58 1.75 5.26 8.77 13.45 13.45 7.60 12.28 Mean 91.00 0.57 1.391.81 1.99 2.28 1.41 −2.30 −0.54 value sem 6.80 1.99 1.83 2.25 2.72 3.422.62 2.53 2.93

TABLE 2 Influence of 10 μg Tiotropium Bromide on the Heart Frequency ofNarcotized Dogs After Inhalative Application via Respimat ®, n = 6Minutes after application Control 1 5 10 20 30 60 120 180 Heartfrequency (beats/min.) 66.50 79.00 75.00 75.00 77.00 79.00 74.00 75.0070.00 87.50 96.00 91.00 88.00 89.00 90.00 85.00 83.00 83.00 86.50 85.0080.00 79.00 77.00 76.00 75.00 76.00 87.00 109.50 104.00 102.00 101.00101.00 101.00 103.00 103.00 105.00 110.50 102.00 102.00 102.00 101.0096.00 101.00 102.00 101.00 85.50 76.00 75.00 76.00 77.00 74.00 73.0074.00 74.00 Mean 91.00 90.33 87.50 86.83 87.00 86.00 85.17 85.50 86.67value sem 6.80 4.89 5.17 5.00 4.82 4.60 5.61 5.53 5.75 10 μg tiotropiumbromide, % alteration 66.50 18.80 12.78 12.78 15.79 18.80 11.28 12.785.26 87.50 9.71 4.00 0.57 1.71 2.86 −2.86 −5.14 −5.14 86.50 −1.73 −7.51−8.67 −10.98 −12.14 −13.29 −12.14 0.58 109.50 −5.02 −6.85 −7.76 −7.76−7.76 −5.94 −5.94 −4.11 110.50 −7.69 −7.69 −7.69 −8.60 −13.12 −8.60−7.69 −8.60 85.50 −11.11 −12.28 −11.11 −9.94 −13.45 −14.62 −13.45 −13.45Mean 91.00 0.49 −2.93 −3.65 −3.30 −4.14 −5.67 −5.26 −4.24 value sem 6.804.68 3.84 3.66 4.25 5.23 3.84 3.86 2.70

TABLE 3 Influence of 3 μg Formoterol Fumarate on the Heart Frequency ofNarcotized Dogs After Inhalative Application via Respimat ®, n = 6Minutes after application Control 1 5 10 20 30 60 120 180 Heartfrequency (beats/min.) 94.50 102.00 105.00 129.00 134.00 138.00 134.00115.00 108.00 133.00 123.00 140.00 162.00 165.00 159.00 153.00 147.00140.00 60.00 67.00 64.00 100.00 95.00 89.00 86.00 88.00 86.00 80.5091.00 95.00 110.00 100.00 95.00 94.00 94.00 96.00 106.50 129.00 137.00138.00 141.00 145.00 140.00 130.00 130.00 92.50 107.00 116.00 125.00126.00 128.00 128.00 120.00 120.00 Mean 94.50 103.17 109.50 127.33126.83 125.67 122.50 115.67 113.33 value sem 10.03 9.19 11.59 8.89 10.7111.44 10.87 9.02 8.39 3 μg formoterol fumarate, % alteration 94.50 7.9411.11 36.51 41.80 46.03 41.80 21.69 14.29 133.00 −7.52 5.26 21.80 24.0619.55 15.04 10.53 5.26 60.00 11.67 6.67 66.67 54.33 48.33 43.33 46.6743.33 80.50 13.04 18.01 36.65 24.44 18.01 16.77 16.77 19.25 106.50 21.1328.64 29.58 32.39 36.15 31.46 22.07 22.07 92.50 15.68 25.41 35.14 36.2238.38 38.38 29.73 29.73 Mean 94.50 10.32 15.85 37.72 36.17 34.41 31.1324.58 22.32 value sem 10.03 3.99 3.99 6.24 5.25 5.28 5.10 5.12 5.36

TABLE 4 Influence of 10 μg Formoterol Fumarate on the Heart Frequency ofNarcotized Dogs After Inhalative Application via Respimat ®, n = 6Minutes after application Control 1 5 10 20 30 60 120 180 Heartfrequency (beats/min.) 94.50 116.00 153.00 155.00 157.00 159.00 163.00176.00 152.00 133.00 145.00 136.00 191.00 204.00 207.00 210.00 209.00205.00 60.00 109.00 146.00 152.00 153.00 150.00 149.00 146.00 141.0080.50 96.00 120.00 144.00 156.00 156.00 140.00 140.00 130.00 106.50105.00 120.00 160.00 158.00 150.00 150.00 145.00 145.00 92.50 122.00122.00 130.00 135.00 140.00 140.00 135.00 135.00 Mean 94.50 115.50132.83 155.33 160.50 160.33 158.67 158.50 151.33 value sem 10.03 6.945.88 8.32 9.38 9.70 10.83 11.68 11.18 10 μg formoterol fumarate, %alteration 94.50 22.75 61.90 64.02 66.14 68.25 72.49 86.24 60.85 133.009.02 2.26 43.61 53.38 55.64 57.89 57.14 54.14 60.00 81.67 143.33 153.33155.00 150.00 148.33 143.33 135.00 80.50 19.25 49.07 78.88 93.79 93.7973.91 73.91 61.49 106.50 −1.41 12.68 50.23 48.36 40.85 40.85 36.15 36.1592.50 31.89 31.89 40.54 45.95 51.35 51.35 45.95 45.95 Mean 94.50 27.2050.19 71.77 77.10 76.65 74.14 73.79 65.59 value sem 10.03 11.86 20.7017.32 17.15 16.44 15.70 15.77 14.42

TABLE 5 Influence of the Combination of 3 μg Tiotropium Bromide + 3 μgFormoterol FU on the Heart Frequency of Narcotized Dogs After InhalativeApplication via Respimat ®, n = 6 Minutes after application Control 1 510 20 30 60 120 180 Heart frequency (beats/min.) 107.50 107.00 110.00112.00 110.00 110.00 110.00 106.00 106.00 143.00 153.00 162.00 160.00158.00 154.00 161.00 146.00 145.00 95.00 106.00 109.00 111.00 121.00119.00 108.00 114.00 107.00 95.50 110.00 117.00 129.00 128.00 130.00129.00 123.00 123.00 112.00 127.00 120.00 115.00 115.00 104.00 112.00107.00 96.00 101.50 100.00 110.00 110.00 112.00 114.00 110.00 101.0095.00 Mean 109.08 117.17 121.33 122.83 124.00 121.83 121.67 116.17112.00 value sem 7.31 8.07 8.33 7.69 7.31 7.37 8.47 6.73 7.78 3 μgtiotropium bromide + 3 μg formoterol fumarate, % alteration 107.50 −0.472.33 4.19 2.33 2.33 2.33 −1.40 −1.40 143.00 6.99 13.29 11.89 10.49 7.6912.59 2.10 1.40 95.00 11.58 14.74 16.84 27.37 25.26 13.68 20.00 12.6395.50 15.18 22.51 35.08 34.03 36.13 35.08 28.80 28.80 112.00 13.39 7.142.68 2.68 −7.14 0.00 −4.46 −14.29 101.50 −1.48 8.37 8.37 10.34 12.328.37 −0.49 −6.40 Mean 109.08 7.53 11.40 13.17 14.54 12.76 12.01 7.423.46 value sem 7.31 2.91 2.87 4.86 5.38 6.41 5.12 5.55 6.23

TABLE 6 Influence of the Combination of 10 μg Tiotropium Bromide + 10 μgFormoterol Fumarate on the Heart Frequency of Narcotized Dogs AfterInhalative Application via Respimat ®, n = 4 Minutes after applicationControl 1 5 10 20 30 60 120 180 Heart frequency (beats/min.) 107.50107.00 107.00 114.00 117.00 117.00 117.00 116.00 119.00 143.00 150.00154.00 171.00 180.00 182.00 181.00 168.00 168.00 95.00 107.00 107.00116.00 124.00 127.00 125.00 122.00 126.00 95.50 116.00 117.00 120.00127.00 129.00 130.00 120.00 123.00 Mean 110.25 120.00 121.25 130.25137.00 138.75 138.25 131.50 134.00 value Sem 11.29 10.22 11.17 13.6414.49 14.65 14.50 12.23 11.42 10 μg tiotropium bromide + 10 μgformoterol fumarate, % alteration 107.50 −0.47 −0.47 6.05 8.84 8.84 8.847.91 10.70 143.00 4.90 7.69 19.58 25.87 27.27 26.57 17.48 17.48 95.0012.36 12.36 22.11 30.53 33.68 31.58 28.42 32.63 95.50 21.47 22.51 25.6532.98 35.08 36.13 25.65 28.80 Mean 110.25 9.63 10.59 18.35 24.56 26.2225.78 19.87 22.40 value sem 11.29 4.77 4.80 4.29 5.44 6.04 5.97 4.615.06

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the influence of 3 μg formoterol fumarate, 3 μg tiotropiumbromide and a combination of 3 μg tiotropium bromide+3 μg formoterolfumarate on the bronchial resistance of narcotized dogs, n=6.

FIG. 2 shows the influence of 10 μg formoterol fumarate, 10 μgtiotropium bromide and a combination of 3 μg tiotropium bromide +3 μgformoterol fumarate on the bronchial resistance of narcotized dogs, n=6.

We claim:
 1. A pharmaceutical composition comprising: (a) tiotropiumbromide; and (b) formoterol fumarate.
 2. The pharmaceutical compositionaccording claim 1, wherein the pharmaceutical composition is inhaled. 3.A process for the production of a pharmaceutical composition accordingto claim 1, comprising: (a) mixing tiotropium bromide, and formoterolfumarate; and optionally (b) adding an adjuvant and/or carriermaterials.
 4. A method of treating respiratory ailments by administeringto a host in need of such treatment a pharmaceutical compositionaccording to claim
 1. 5. The method according to claim 4, wherein therespiratory ailment is asthma or chronic obstructive pulmonary disease(COPD).